A 62-year-old Chinese man was admitted for progressive weakness, loss of weight and appetite, and multiple neurologic deficits.
History of the presenting symptom
The patient had a 6-month history of unsteady gait and generalized weakness with constitutional symptoms of loss of weight and appetite. He consulted his general practitioner 2 months later. Laboratory investigations then showed normal complete blood count and liver and thyroid function tests. Magnetic resonance imaging (MRI) of the brain with contrast fluid-attenuated inversion recovery (FLAIR) sequences and diffusion-weighted imaging showed multiple nonspecific foci of an abnormal signal seen in the white matter of both cerebral hemispheres. VDRL serology was nonreactive. The only abnormal investigation was an elevated serum sodium level at 148 mmoles/liter (reference interval 135–145). He was referred to a neurologist, who made a diagnosis of multiple system atrophy based on features of cerebellar dysfunction and dysautonomia, which included orthostatic hypotension and erectile dysfunction. His serum vitamin E level was 11.3 mg/liter (reference interval 5.5–18.0). He was commenced on high-dose oral vitamin E therapy as an antioxidant for multiple system atrophy. He subsequently presented to the general medicine department and was admitted for progression of symptoms.
He had been attending long-term followup visits with his general practitioner for hyperlipidemia and type 2 diabetes mellitus for >10 years. Glycosylated hemoglobin (HbA1c) 2 months prior to admission was 11.8%. His regular medications included lovastatin, glipizide, and vitamin E tablets. He had no recent exposure to anyone with tuberculosis or history of pulmonary tuberculosis.
Medications and allergies
He did not consume any over-the-counter medications or traditional herbal preparations. He was adherent to his medications, but not to dietary control for diabetes mellitus and hyperlipidemia.
Social and family history
The patient was born in Singapore and was the fourth of 10 children. There was a family history of hypertension and hyperlipidemia, but no history of neurologic disease or malignancy. His younger sister had died of an unknown complication of systemic lupus erythematosus (SLE) 2 decades before. He was single and living with his father. He was retired and used to work as a taxi driver. He did not smoke tobacco or consume any ethanol or illicit drugs.
Review of systems
The patient experienced a week's duration of change in bowel habit in the form of intermittent constipation. There was no per rectal bleeding, blood mixed with stools, chest pain, shortness of breath, abdominal pain, chronic cough, or any change in micturition. There was no history of joint pain, oral ulcers, alopecia, photosensitivity, Raynaud's phenomenon, or fever.
Examination upon admission revealed a thin man who weighed 45 kg. He appeared lethargic, but was alert, coherent, nontoxic, and apyrexial. He was noted to have significant postural hypotension: his supine blood pressure was 117/75 mm Hg and pulse rate was 90 beats/minute, and his standing blood pressure was 83/71 mm Hg and pulse rate was 76 beats/minute. Hydration was assessed to be adequate. There was a paucity of facial expression, xanthelasma, and dry mucous membranes. Cardiac examination revealed normal heart sounds with no murmurs. Chest auscultation revealed vesicular breath sounds with no adventitious sounds. His abdomen was soft, with no detectable organomegaly. Digital rectal examination showed brown stools with no rectal masses or blood. Neurologic assessment showed bilateral dysmetria and dysdiadochokinesia of both the upper and lower extremities. Tone and deep tendon reflexes were normal. Plantar responses were flexor. There was no resting tremor, cogwheel rigidity, bradykinesia, lead-pipe rigidity, or postural instability. Power was grade 4 of 5 (Medical Research Council power grading) in all 4 extremities proximally and distally, with no loss in sensation or proprioception. There were no cranial neuropathies or nystagmus. His peripheral pulses were well felt symmetrically. There were no palpable lymph nodes, rash, joint swelling, alopecia, mouth ulcers, parotidomegaly, or pedal edema.
Initial laboratory evaluation
The results of his initial laboratory evaluation are shown in Table 1. Chest radiography showed clear lung fields with no cardiomegaly or hilar enlargement. His electrocardiogram revealed normal sinus rhythm, with a ventricular rate of 65/minute. A computed tomography scan of his brain revealed background involutionary changes with chronic microvascular ischemic changes.
Table 1. Initial laboratory results*
WBC = white blood cell; ESR = erythrocyte sedimentation rate; ALT = alanine aminotransferase; AST = aspartate aminotransferase; CRP = C-reactive protein; HDL = high-density lipoprotein; LDL = low-density lipoprotein; ↑ = increase; FEME = formed elements and microscopic examination; CEA = carcinoembryonic antigen; PSA = prostate-specific antigen; LDH = lactate dehydrogenase.
WBC count, × 109/liter
Platelets, × 109/liter
Total protein, gm/liter
Alkaline phosphatase, units/liter
Calcium (corrected), mmoles/liter
HDL cholesterol, mmoles/liter
LDL cholesterol, mmoles/liter
Glycosylated hemoglobin, %
CA 19-9 antigen, ml
A 62-year-old Chinese man was admitted for progressive weakness, loss of weight and appetite, postural hypotension, and bilateral cerebellar signs. Initial laboratory results showed mild hypernatremia and an elevated HbA1c.
He underwent a colonoscopic examination in view of his constitutional symptoms of loss of weight and appetite, intermittent constipation, and iron and vitamin B12 deficiency anemia. The results of the examination were normal.
On the third day of his inpatient stay, he developed shortness of breath, with tachypnea of 24 breaths/minute. He was assessed to be dehydrated, his blood pressure was 100/68 mm Hg, and his pulse rate was 95 beats/minute. There were no other new clinical findings. He was found to have progressive hypernatremia with compensated high anion gap metabolic acidosis. The laboratory tests done are shown in Table 2. Metformin was discontinued. Intravenous fluids were increased.
Table 2. Laboratory results from days 3 and 4*
↑= increase; ↓ = decrease.
Urine osmolality, mmoles/liter
Po2, mm Hg
Pco2, mm Hg
Base excess, mmoles/liter
On the fourth day, the patient experienced another episode of hypotension, with a systolic blood pressure of 80 mm Hg. He was clinically dehydrated and it was noted that his urine output had been 5.4 liters the day before and 3 liters on the same day by noon. This was corrected with intravenous crystalloids. His serum sodium level was 165 mmoles/liter and urine osmolality was found to be inappropriately dilute at <130 mmoles/liter (reference interval 500–1,200). The diagnosis of neurogenic diabetes insipidus (NDI) was confirmed after 2 μg of intravenous desmopressin resulted in a rise in urine osmolality to 453 mmoles/liter. Prolactin levels were normal, as were the rest of the hormones produced by the adenohypophysis. MRI of the pituitary gland showed interval development of the thickened, enhancing pituitary stalk, suggestive of hypophyseal infiltration (arrow in Figure 1A), and a second, smaller enhancing lesion in the posterior fossa (Figure 1B).
The patient is an elderly man with progressive weakness, loss of weight and appetite, cerebellar dysfunction, and new development of NDI. The possible diagnoses to unite all of these factors include neoplastic, infiltrative, infectious, and rheumatic etiologies (Table 3).
Table 3. Differential diagnoses
Metastatic: lung, gastrointestinal tract, thyroid
Primary central nervous system lymphoma
Paraneoplastic cerebellar degeneration: small cell lung carcinoma, neuroblastoma, thymoma, and teratoma
Metastases to the pituitary gland in men arise most commonly from bronchogenic carcinoma (), whereas other common primary sites include the gastrointestinal tract and thyroid. Another clue to point to the possibility of cerebral metastases is the presence of NDI itself. Because the neurohypophysis derives its arterial supply almost directly from the internal carotid artery via the inferior hypophyseal arteries, there is a predilection for malignant cells to first spread to and then infiltrate or cause microinfarction of the posterior stalk compared to the adenohypophysis, which obtains its arterial supply via a portal system ([2, 3]). The presence of stalk thickening on MRI is also a hallmark of pituitary involvement by distant spread, which is a feature uncommonly seen in benign pituitary adenomas ().
Apart from solid organ malignancies, a primary lymphoma arising from the central nervous system (CNS) can also cause a similar clinical presentation. Intracranial CNS lymphomas have been reported to cause cerebellar dysfunction in 20% and involve the pituitary gland in 3% of patients ().
Paraneoplastic cerebellar degeneration is also a well-reported cause of cerebellar dysfunction associated with malignancy. In such patients, antibodies directed against P/Q-type voltage-gated calcium channels or C-terminal of the metabotropic glutamate receptor 1 may be detected ([6, 7]). Malignancies that cause CNS paraneoplastic neurologic syndromes include small cell lung carcinoma, neuroblastoma, thymoma, and teratoma (). Lymphomas, on the other hand, are more likely to cause paraneoplastic manifestations involving the peripheral nervous system ().
Sarcoidosis is a well-known infiltrative disease of noncaseating granulomata where neurologic manifestations are well reported. Neurosarcoidosis commonly presents with cranial neuropathies and small fiber neuropathy (). Hypothalamic–pituitary involvement () is known to cause diabetes insipidus due to the development of granulomas confined to the neurohypophysis. Cases of cerebellar () and cerebellopontine angle () involvement have also been reported. The lack of other neurologic findings, stigmata of systemic sarcoidosis, and the classic MRI findings of periventricular white matter lesions surrounding areas of leptomeningeal enhancement () make this diagnosis less likely. The mild hypercalcemia is likely to be due to the patient's dehydrated state. Nonetheless, tissue histology demonstrating noncaseating granulomata is crucial to the diagnosis of neurosarcoidosis. Supportive investigations such as serum angiotensin-converting enzyme may be useful provided levels are elevated.
Langerhans' cell histiocytosis is an uncommon disease due to clonal proliferation of histiocytes resulting in granulomatous deposits in various sites of the body. It has been described to involve the hypothalamic–pituitary axis and cause NDI in particular, where again thickening of the pituitary stalk on MRI is a feature (). However, the presence of cerebellar involvement, absence of painful bony swellings, cutaneous involvement, palpable lymphadenopathy, and abnormalities on chest radiograph make this diagnosis unlikely. Cases of non–Langerhans' cell histiocytosis (Erdheim-Chester disease) presenting with lesions in the pituitary and cerebellum, constitutional symptoms, and diabetes insipidus also have been reported ().
Human immunodeficiency virus (HIV) infection has been known to cause a wide spectrum of neurologic manifestations. It is associated with pituitary gland dysfunction of both the adenohypophysis and neurohypophysis. Cases of lymphocytic hypophysitis (), JC virus variant–associated cerebellar atrophy (), cerebellar involvement from opportunistic infections such as cryptococcal meningitis (), and cerebral toxoplasmosis () have been reported. In this case, HIV antibody tested negative.
Tuberculosis is an infection endemic in Southeast Asia, and CNS tuberculosis is the most feared form of extrapulmonary tuberculosis because of its devastating sequelae. Intrasellar tuberculomas resulting in NDI have been reported (). Histology and culture of the suspected lesion and examination of the cerebrospinal fluid (CSF) for lymphocytic inflammation and Mycobacterium tuberculosis cultures would be essential to diagnose CNS tuberculomas and/or meningitis.
Sjögren's syndrome (SS) characterized by lymphocytic infiltration of the exocrine glands most commonly affects the salivary and lacrimal glands, resulting in classic sicca symptoms. The American–European Consensus Group classification criteria for SS () are presently being challenged for lacking in sensitivity and specificity (). It has been proposed that the case definition require at least 2 of the following 3 criteria (): 1) positive serum anti-SSA and/or anti-SSB or (positive rheumatoid factor and antinuclear antibody titer >1:320), 2) ocular staining score >3, and 3) presence of focal lymphocytic sialadenitis with a focus score of >1 focus/4 mm2 in labial salivary gland biopsy samples.
CNS manifestations in primary SS are diverse. White matter hyperintensity has been described in brain FLAIR MRI sequences (). Patients positive for anti–aquaporin 4 antibodies appear to have involvement of the optic nerve, cerebrum, and brainstem, with cervical posterior column lesions in the spinal cord, presenting with the neuromyelitis optica spectrum of disease (). Aseptic meningitis can occur, resulting in diffuse leptomeningeal enhancement as in the MRI of our patient's brain, whereas the white matter hyperintensity may be part of CNS SS. Cases of SS with hypertrophic pachymeningitis, lymphocytic hypophysitis (), and coexistence with sarcoidosis have been reported ().
Although SLE would be another differential diagnosis, the absence of other clinical features of SLE and hematologic abnormalities, normal urine sediments and dipsticks, normal serum complement, and negative anti–double-stranded DNA and antiphospholipid antibodies made this diagnosis less likely.
Systemic vasculitis is another rheumatic disease to consider as an etiology in this case. Granulomatosis with polyangiitis (Wegener's) (GPA) is an antineutrophil cytoplasmic antibody (ANCA)–associated systemic vasculitis involving both medium and small vessels. CNS involvement occurs in 10–45% of GPA patients, commonly presenting as strokes and seizures because of cerebral vasculitis or granulomatous manifestations affecting CNS structures (). Cases of NDI as a manifestation of GPA have been reported since the 1990s (). In fact, when there is pituitary involvement in GPA, 96% of cases have at least one other concomitant organ system being involved, with the upper respiratory tract being the most frequent site (93%), followed by the lungs (73%) and kidneys (67%) (). In other words, isolated pituitary involvement in GPA is rare. In our patient, there were no other clinical, laboratory, or radiographic features suggestive of GPA.
ADDITIONAL HOSPITAL COURSE
A computed tomography scan of the posterior nasal space, thorax, abdomen, and pelvis did not reveal any neoplasms or lymphadenopathy, apart from fatty infiltration of the liver. Nasoendoscopy was normal. Lumbar puncture showed clear and colorless CSF, opening pressure of 5 cm of water, red blood cells <1/μliter (reference value <1), nucleated cells 2/μliter (reference interval 0–5), total protein of 0.39 gm/liter (reference interval 0.10–0.40), glucose of 4.2 mmoles/liter (reference interval 2.5–5.5), and capillary glucose of 8.8 mmoles/liter. Smears and cultures for bacteria, mycobacteria, and fungi were all negative; the Cryptococcus neoformans antigen test was negative. CSF tetraplex polymerase chain reaction did not reveal any cytomegalovirus, herpes simplex virus, varicella-zoster virus, and Toxoplasma gondii. No malignant cells were seen. CSF did not reveal any oligoclonal bands.
Neurosurgical opinion was that a tissue biopsy of the pituitary stalk or any of the lesions in the posterior fossa would involve a high risk of morbidity and was therefore abandoned. It was then decided to further evaluate for systemic rheumatic disease when the antinuclear antibody test came back as 1:320 and speckled. ANCA tested negative. The patient was noted to have a diminished salivary pool and on further questioning revealed that he had dry eyes. Schirmer's test without anesthesia was positive for dry eyes (<5 mm in 5 minutes for both eyes). Measurement of oral salivary flow was not carried out. Anti-Ro antibody was subsequently found to be positive. Serum complement 4 level was normal. Autonomic function tests revealed the presence of dysautonomia, and nerve conduction tests showed peripheral neuropathy. Anti–aquaporin 4 antibodies tested negative. Other relevant laboratory tests are shown in Table 4. Minor salivary gland biopsy showed at least 1 focus of intralobular aggregates of >50 lymphocytes within 4 mm2 of mucinous glandular tissue. Features were those of focal lymphocytic sialadenitis with a focus score of >1 (Figure 2).
Table 4. Subsequent laboratory results*
↑= increase; ACE = angiotensin-converting enzyme; HBsAg = hepatitis B surface antigen; anti-HBcAb = anti–hepatitis B core antibody HCV = hepatitis C virus; HIV = human immunodeficiency virus; ANA = antinuclear antibody; ANCA = antineutrophil cytoplasmic antibody; anti-dsDNA = anti–double-stranded DNA; anti-ENA = anti–extractable nuclear antigen; aCL = anticardiolipin antibodies.
No paraprotein band
ACE level, units/liter
Rapid plasma reagin
Complement 4, gm/liter
Primary SS complicated by CNS involvement with cerebellar dysfunction, leptomeningeal enhancement, lymphocytic hypophysitis, and dysautonomia.
This case emphasizes the importance of considering primary SS with CNS involvement in a patient with progressive neurologic deficits, NDI, and constitutional symptoms. Patients often do not report symptoms of dry eyes unless specifically asked. Dry eyes due to reduced lacrimal gland tear production are not uncommon in the elderly. The prevalence of CNS manifestations in primary SS is debatable. This is evident from the reported prevalence, which ranges from 0–100% of all cases in different studies (). This can be accounted for by various reasons, such as there being no consensus criteria for the diagnosis of CNS disease in primary SS and the inclusion of psychiatric disorders as CNS involvement. CNS disease in primary SS tends to occur in a bimodal fashion (), both at the onset of disease and subsequently, with a mean age at onset of 53 years in a retrospective study conducted in an Italian population (). Lung disease, disease duration, and low C4 appeared to be risk factors for CNS SS.
Nervous system involvement in primary SS can be divided into that afflicting the peripheral nervous system or CNS. Peripheral nervous system involvement is more common, presenting with sensory neuropathy, mononeuropathy, polyneuropathy, or pan-dysautonomia. It is possible that the patient's dysautonomia may be attributed in part to diabetic neuropathy as a result of poor glycemic control. Diffuse CNS disease may manifest as encephalopathy, seizure, cognitive dysfunction, or aseptic meningitis. Focal CNS involvement can present as transverse myelopathy, motor or sensory deficits, a brainstem syndrome, migraine, or in this instance, a cerebellar syndrome. Multiple sclerosis–like illness and isolated optic neuritis are other forms of intracranial pathology in primary SS. Neurologic involvement frequently has been reported to precede the subsequent diagnosis of SS (). Therefore, a high index of clinical suspicion is necessary, in particular asking for a history of sicca symptoms.
The utility of MRI in the delineation of CNS involvement in primary SS is unclear. Nonspecific T2-weighted hyperintensity was demonstrated in most patients with focal CNS involvement ([35, 36]), but is less likely to pick up pathologies in diffuse CNS disease. However, the findings for the former are not specific for CNS disease in SS. Frontal white matter microstructure alterations on MRI have been found to be associated clinically with mild cognitive impairment in some studies ().
With regard to SS causing lymphocytic hypophysitis, this is the second such report documenting this association. Li et al () first reported a case of NDI secondary to lymphocytic hypophysitis and hypertrophic pachymeningitis secondary to primary SS. We believe that the cause for our patient's onset of NDI is due to the primary SS for 2 main reasons. First, the thickening of the pituitary stalk on MRI is typical of lymphocytic hypophysitis (). Second, an extensive search for a primary malignancy to account for pituitary metastases did not reveal any remarkable findings. Unfortunately, the pituitary stalk thickening only marginally improved following immunosuppressive therapy. The patient also remains dependent on intranasal desmopressin.
There are no randomized controlled studies on the treatment of CNS involvement and autoimmune hypophysitis with NDI in primary SS (). Since the postulated mechanism is likely to be associated with CNS vasculitis, the treatment modalities are mostly extrapolated from the treatment of SLE with CNS involvement, including high-dose corticosteroids, cyclophosphamide (), and recently, rituximab ().
SUBSEQUENT CLINICAL COURSE
The patient was commenced on desmopressin for his NDI and intravenous pulse methylprednisolone 500 mg/day for 3 days followed by monthly intravenous cyclophosphamide for 3 months. In the third week of hospitalization, he developed acute left hemiparesis from sagittal sinus thrombosis. He tested negative for IgG and IgM anticardiolipin antibodies and anti–β2-glycoprotein I. Protein C, protein S, anti–thrombin III, and activated protein C resistance test were all normal. He received warfarin for the next year and remains on warfarin, since repeat brain MRI showed chronic sagittal sinus thrombosis. He unfortunately only recovered from the left hemiparesis, and not the cerebellar dysfunction and peripheral neuropathy. He has remained homebound and is able to stand with assistance and walk with a walking frame. However, he continues to require assistance in his activities of daily living. He also remains dependent on long-term intranasal desmopressin, and his SS is presently quiescent on prednisolone 5 mg/day and hydroxychloroquine 200 mg/day. Rituximab was not given in this case, since he responded to high-dose corticosteroids and intravenous cyclophosphamide with normalization of erythrocyte sedimentation rate. The cost of the medication was the other consideration.
He has developed osteoporosis from immobility and as a result of glucocorticoid use, with a vertebral fracture sustained following a fall. He is presently receiving yearly intravenous zoledronic acid and elemental calcium/vitamin D supplementation.
All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. Dr. Thong had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study conception and design. Joel Hua-Liang Lim, Chia, Thirugnanam, Thong.
Acquisition of data. Joel Hua-Liang Lim, Chia, Tchoyoson Choie-Cheio Lim, Thirugnanam, Thong.
Analysis and interpretation of data. Joel Hua-Liang Lim, Chia, Tchoyoson Choie-Cheio Lim, Ho, Thirugnanam, Thong.